1. Field of the Invention
The present invention generally relates to the fields of bacteriology and infectious diseases. More specifically, it relates to inhibitors of certain bacterial signaling mechanisms and bacterial infection treatments using these inhibitors.
2. Description of Related Art
Treatment of bacterial infections typically involves administration of one or more antibiotics. These agents, while often initially effective, may cause development of bacterial resistance to one or more types of antibiotics. Indeed, multi-drug resistant bacterial infections are a significant health concern throughout the world. Treatment methods that effectively eliminate bacterial infections without inducing bacterial resistance are therefore needed.
Quorum sensing (QS) is a mechanism that allows bacteria to respond to hormone-like molecules called autoinducers (AI) and is responsible for controlling a plethora of virulence genes in several bacterial pathogens. Because QS is not directly involved in essential processes such as growth of the bacteria, inhibition of QS should not yield a selective pressure for development of resistance (Rasmussen and Givskov, 2006).
A signaling cascade in enterohemorrhagic E. coli O157:H7 (EHEC) has been previously reported and is involved with QS by signaling with autoinducer-3 (AI-3) (Clarke et al., 2006). The AI-3/epinephrine (epi)/norepinephrine (NE) inter-kingdom signaling cascade activates expression of the flagella regulon (necessary for the bacteria to swim through the mucus layer, and reach the epithelial barriers), the LEE genes (encodes a specialized secretory pathway, through which bacteria secrete toxins to the mammalian cells, which culminate in diarrhea) and Shiga toxin genes (responsible for hemolytic uremic syndrome (HUS)) in EHEC (Sperandio et al., 2003; Clarke et al., 2006; Walters et al., 2006). AI-3 and epinephrine/NE are agonistic signals, and response to both signals can be blocked by adrenergic antagonists such as phentolamine or propranolol (Sperandio et al., 2003; Clarke et al., 2006; Walters et al., 2006; Walter and Sperandio, 2006). These signals are sensed by sensor kinases in the membrane of EHEC that relay this information through a complex regulatory cascade that activates the expression of the flagella regulon, the LEE genes and Shiga toxin. QseC (Quorum sensing E. coli regulator C) is one of these sensor kinases. QseC specifically senses AI-3/epinephrine and NE to augment its phosphorylation state, and that QseC directly binds to NE (Clarke et al., 2006). QseC's recognition of these signals can be blocked with the α-adrenergic antagonist phentolamine (Clarke et al., 2006). The QseC regulon is very complex and is intrinsically involved in the regulation of all known, and potentially several unknown, EHEC virulence genes.
Manipulation of QseC and/or the AI-3/epi/NE signaling cascade may offer a means of controlling bacterial virulence and thus, bacterial infections. Such means may minimize the probability of inducing bacterial resistance relative to conventional antibiotics. Agents that modulate these systems therefore merit investigation. Early work in the area of blocking the quorum sensing signals has been carried out by the current inventors. This work showed that a lead molecule LED209 can block the QseC response to the signal in U.S. Pat. No. 8,252,841, which is incorporated herein by reference. In that scenario, the LED209 small molecule and α-adrenergic antagonist (phentolamine; PE) block this response while β-adrenergic antagonist does antagonize the QseC recognition of a signal (Clarke et al., 2006, Rasko et al., 2008). However, additional compounds with distinct or improved activity are desired.
Furthermore, in addition to molecules that can decrease virulence, compounds which also modulate the activity of bacterial by increasing their virulence could be useful research tools. Such compounds could aid in the advancement of the understanding of quorum sensing and how virulence is regulated by quorum sensing and its related chemical signals.